Synthesis of vitamin a



Patented Feb. 13, 1945 UNITED STATES PATENT orrlcs r 2,369,165 smnasrs OF vmmm .4

Nicholas A. Milas, Belmont, Mass, aasimor to Research Corporation, New York, N. Y., a corporation of New York No Drawing. Application March 3, 1942. Serial No. 433,231

(Cl. zen-s11) Claims.

The general object of the present invention is to provide a novel process for the synthetic production of vitamin A and a. number of related intermediate products.

The accepted chemical structure of vitamin A is represented by the formula:

or benzene as solvents, thereby producing Compound II, Equation A.

EQUATION A CH: CH1

which reacts with the sodium ethylate yieidine Compound II.

In the second step, Compound II is sapcnifled with 10% alcoholic potash and the resulting glycldic acid, Compound III, Equation B, is separated and decarboxylated by distillation to produce i-[2',6',6-trimethyl cyclohexene-1-yll-3- rnethyl buten-1-al-4, Compound IV, Equation C.

EQUATION B K Compound 11+ A Compound I EQUATION C CH: CH: OH:

H H H Distillation H C=C C=0+C0| Compound XIH- -----i H H CH:

Compound IV Compound IV may be prepared also by con- (lensing, in an ethereal solution, fl-ionone with ethyl dichioroaeetate (ChCHCOOCaHs) in the presence of dilute magnesium amalsam, yielding Compound Ila, Equation D, which latter may be saponified with alcoholic potash and the resultin: saponlfication produce decarboxylatedto Product IV as in Equations B and C.

EQUATION D CH: CH:

CH: H H 4) H CIICHCOOCQH H C=C -C-CO0C|li| p-ionono-l- Mg-Hg I H l Campoundllc Here it will be seen that Compound 11a is identical with the intermediate product of Equation A and when this Product 11a is subjected to saponificatlon with alcoholic KOI-I as in Equation B, it is simultaneously or successively converted into Compound 11 and Compound III. I

Instead of decarboxylating Compound III by distillation as described above, Compound III is mixed with two molecular equivalents of pyridine and the resultin pyridine salt distilled under a pressure of about 1 mm. and the fraction di8- tilling at about from C. to 103 C. (Compound We) collected. This fraction (Compound Iva) serves in the remainder of the process described hereinafter in the same way as Compound IV but evidence, such as its boiling point, spectroscopid examination, andabsence oi aldehydie properties, indicates that it isnot Compound IV buts, compoimd of the formula V cm cm H E a 1! 0 0- ----CH Compound 1V0 In the third step, Compmmd IV or Compound we is condensed with sodium or lithium acetyiide inamixture oi'etherandliqutdammoniant temperatures between 55' and -'I0' C. After the reaction is over, the ammonie is removed and the produottreated with a dilute solution or tartaric acid, aithouehsuueous soluof ammonium sulfate. ammonium chloride or otheroraanic acids may aleobe used. theresultinz Compound V-or Va. motions EandEoJsextrootedtromthiemixtureinon im ure ztote and maybe purified either by hls vacuum distillation in an inert atmosphere or by preparing its phthalic acid ester by reactinz the mixture with phthalic anbydride in pyridine solution. The phthalic acid ester is subsequently eeponified to obtain the pure acetylene carbinols,

Compound V or Compound Va. EQUATION E CH: CH: CH:

H H H NaCECH H C=C-- #0503 CompoundIV -,o v

iniiggid N H CH:

Cbmpould V EQUA'I'ICI EA w CH: CH:

If n 'n NsCECH H 0-0-4':--o-ezcn Compound IVo n H ..o inliuid N s CH4 Compound Va momma 1" Compound IV HCECMgX Compound V or or Compound Ive (X stsndsfor halogen) Compound W In the iourth s ep, Compoimd V or Vo my be dehydratedby dis'tfliin: under hizh vaeuumwith small amounts oi naphthalene sulionio acid or p-toiuene sulronic acid yielding Compound VII directly (see Equation G) EQUATION G Compound V vacuum or --o Compound VII (see Equation I) Compound Vo dietlllotlon dehydration catalysts Thus it will be seen that both Compotmds IV and We may betreatedin theeame monnerto yield Compound VII.

aemon However, better yields of Compound VII are obtained by preparing from Compounds V and Va the halides thereof, Compounds v1 and flu, Equations H and Ho, and subsequently removing hymen halide with alcoholic potash (see Equa. time I and In) It is observed that Equation Ho works best with the chloride, less well with the bromide, and poorly or not at all-with the iodide.

Eouszrmn I CH: CH:

Compound Vi alcohol Compound VII Eons-rm! In Compound Vlo+ 5 Compound VII lloohol Still another method or converting Compound V or Compound Va into Compound V1! is to form the Grignard oi Compound V havinu the formula CH: CH: CH:

H H H B C=C- CCECMgX MgX H CH:

(X stands for halogen) Grignord of Compound V or the Grianard of Compound Va having the formula CH: CHI CH:

(X stands for halogen) Gncmrd of Compound Va and mix either of said Grlgnard compounds with exactly one moi of assuresm the aim step the Grignard or alkali metal acetylide of Compound VII is prepared by allottlng it to react in ether solution with ethyl maz nesiuin bromide or metallic lithium. for example: Tothe'tirignard' or alkali acetylide 01- Compound VII is slowly added methyl vinyl ketone (ennui) whereby the Product VIII is formed (see Equation J).

Eon-none OH: OK:

l 8 CHI 11 K 6 n a n =C- -CCEC(M[BrH-O= C==CH:

or (u) H: v

' oncm H H cm H on H n c-c-o-c-csc-oc=cn,

H OH:

I Compound VIII In the sixth step Compound vm is partially hydrogenated catalytically at room temperature using gaseous hydrogen and palladium black cataiyst-deposited,on calcium carbonate or barium sulfate yielding Compound Ix. Equation K. Another useful method for the partial reduction of Compound VIII to produce Compound I); is the use of an active iron catalyst. made by leaching with alkali the aluminum iroman aluminum-iron alloy, and hydrogen under a pressure of about 50-75 atmospheres and temperatures not higher than 100 C. (see Equation K) EQUATION K H: Compound VIII+ Pd or active iron CH: CH:

CH: H CH;

H CH:

Cb'mpo'lmd IX In the seventh step, Compound IX may be treated with acetic anhydride to form the acetic ester of vitamin A, Compound XI, Equation L.

In this stop any suitable acid anhydride other than acetic anhydride; such as propionic and its higher homologues up to and including palmitic and stearic and other organic acid anhydrides. such as benzoic acid anhydride, could'be employedto produce the corresponding vitamin A esters, any of which may be converted into vitamin A by sapcniilcation, as described hereinafter.

Equal-ion L acetic anhydride Compound XI Compound IX -----u (see Equation N) Better yields of the acetate are obtained when Compound IX is treated first with a halogenating agentsuch as phosphorus tribromide in pyridine yielding Compound X. Equation M. which latter is treated with potassium acetate yielding Compound XI, Equation N.

Inthis step Compound IXv may be treated with any other suitable halogenatin: aaent such as phosphorus ltrichloride or thionyl chloride and the resultingi'nalogen Compound X converted into any desired: organic acid ester-oi vitamin A by treating it with the'aikall metal salt of the desired acid in the presence of the free acid.

Still another method of making the esters or vitamin A isto treat Compound IV or Compound XV'o with acetic or any other suitable organic acid anhydride in the presence of the alkali metal salt of said acid and heat the mixture in vacuum thereby directly producing the acid ester of vital C Hr H C H:

Compound XI The vitamin is finally prepared by saponiiying Compound XI, Equation 0, or by treating Compound x with silver hydroxide (see Equation P).

Bavarian O saponiiy -O alcoholic KGB IO-10 C. in N; atmosphere Eommon 1'' holie solution to 50 C.

Compound XI+ Compound 1 Compound X+ Compound i in alco In the preparation of Compound K1, the following alternative route-may be used: Methyl vinyl ketone is condensed with sodium or lithium aeetylide in liquid ammonia to produce Compound 3 XII, Equation Q. which latter is then converted into the Grignard XIII, Equation R, by interaction with ethyl ium bromide. The Grignard XIII is allowed to react in ether solution with the Compound IV or Iva followed by hydrolysis with y tartaric acid'or ammonium sulfate to produce Compound XIV or mo, Equation 8 or Sc.

EQUATION Q H CH: Kc N H CH;

E I I5 H,c=c-l :=o uic=c-o-c5cn in liquid NHI H Compound XII Eon-non R 70 CHI tCnHrMgX H J Compound XII HQC=C- CCM5X (X stand! lot halogen) Mix 0mm! XIII Ilium-ion 8 iollowedhy hydrolysis with Compound W Oompoimd XXII 11cm rmfldafim CH: CH}

CH: OH: H H H H H H C=GHC--C.=;C- -C=g 1 in in H CH:

, (impound XIV div CompoundXlII Com an o m OH CH: h M

B H 8 cm H H H C C-CCC C-C-C=C H B K H CH:

. CompoundXlVo Compound XIV or xIVo is then partially reduced to Compound XV or ZVo urine the catalysts and conditions described above (see Equa- An alternative method used to prepare Compound XIV or XIVa consists in the interaction of the Grignard of V or V with methyl vinylketone (see Equations U and U4).

EQUATION U Grignard of V CH: CH:

CH; CH. H B H H I O=CH-C-C"=CMgX+O= CH=CH|- XIV l (SMgX H CH3 (X stands ior halogen) Eqwmon Us Gi'ignard oi Va CH: CH:

1 CH: H H J} H H C= -%-CECMBX+O= -CH=CH- Xlvo H CH| MgX or stand! for holom) Compound XV or xva is haioeenated with a suitable agent such as a phosphorus trihalide,

e. g. phosphorus trichloride or tribromide in pyridine at 0 C. yielding Compound XVI or m,

6 Equations W and We, and the latter are dehydrohalogenated, for example, by treating with exactly one moi of potassium hydroxide in alcohol to yield Compound X, Equation Y.

m EQUATION W 0H: CH:

CHI H H H H H A: H PX: H O=O --C-C=G- C-OHX XV --v H Pyridine at 0 C. H: CHI.

i (in which X stands for halogen) Compound XVI 2o Enos-non We CH: CH:

CH: OH: H 2 H H H H PX; H 0:0- OC-C- ===C CHX xv n Pyridine at 0 C. H: CH:

2 (in which X stands [or halogen) Compound XVla so (The above reactions work better with the chloride than with the bromide.)

Eominox Y XVI KOH or e CompoundX XVIo alcohol PREPARATION or Gurcro Es'rnn Conromm II, Fms'r Srrzr, EQUATION A Twenty-four grams of metallic sodium is dissolved in about 300-400 cc. of absolute ethyl alcohol in a one liter filter flask fitted with a reflux condenser. It has been found preferable to add all of the sodium at once and after it had gone into solution, the alcohol is removed under reduced pressure at temperatures ranging irom 160-170". A white sodium ethylate results. This is added slowly to a vigorously stirred mixture of 192 grams of p-ionone, 122 grams ethvl chloroacetate and 110 cc. of anhydrous toluene (benzene may also be used) at 0. After all of the sodium ethylate had been added, stirring is continued until the mixture becomes homogeneous and brownish in color, then allowed to sta d at room temperature for 7-10 hours. It is then heated on the water bath tor 5 hours, cooled to room temperature and acidified with 25% acetic acid. The oil separating from this mixture is fractionated under reduced pressure and the traction boiling at 152-155 (2-3 mm.) collected. A yield of about 80% of Compound II is obtained.

PREPARATION or COMPOUNDS III AND IV, Snoorm S'rsr, Eqoa'rrous B AND C The mixture separates into two layers.

' au ios then dried with anhydrous magnesium sulfate,

'illtered and the ether removed under reduced pressure. The residue (Compound III) is heatedpound III by reaction with pyridine and distillation has been sufllciently described above.

Synthesis of 1-[2',6',6'-trimethyl cyclohereu- .1'wl1-3-methyl S-apozcy butane-1 (Compound Iva) Compound I Va To a mixture of 245 g. (2 mols) of ethyl chloroacetate and 110 g. of anhydrous, sulfur-free toiuene contained in a three-necked, roundbottomed flask equipped with a mercury-sealed stirrer, a thermometer, and a calcium chloride tubeand cooled to about --85 add 192 g. (1 mol) of ,s-ionone. By means of a Gooch rubber connection introduce, over a period of two hours with rapid stirring, 46 g. (2 mols) of finely powderedsodium ethoxide free from alcohol. Bring the-mixture slowly to room temperature by allowing it to stand overnight with moderate stirring in an atmosphere of nitrogen. Continue stirring while the mixture is heated in nitrogen on the water bath for tour hours, then cool to room temperature and neutralize with a solution of 18'! g. of glacial acetic acid in 500 cc. of water. Remove the non-aqueous layer and extract the aqueous layer with two 50 cc. portions of ether and comblue the extracts with the non-aqueous layer. Remove the ether and the toluene and other low boiling constituents by subjecting the mixture to a vacuum distillation (-20 mm.) in an atmosphere of nitrogen at the temperature of boiling water. Cool the residue (Compound II) to room temperature and add to it 840 cc. of 95% alcohol containing 85 g. of potassium hydroxide and reflux the resulting mixture in nitrogen for one hour under a slightly reduced pressure, then remove under reduced pressure approximately twothirds of the alcohol. 0001 the residue and pour it into 1500 cc. of deoxygenated water and extract orthophosphoric acid. Remove other layer and extract non-aqueous layer successively with 200 and 100 cc. of ether and combine ether extracts;

'wash ether extracts twice with 110 cc. portions of water, dry over anhydrous magnesium sulfate, illter and remove ether under reduced pressure.

The residue consists of almost pure s ycidic acid (Compound III) containing small amounts of sethoxy acetic acid.

To decarboxylate the giycidie acid dissolve it in 158 g. (2 mole) of pure anhydrous pyridine and subject the mixture to a vacuum distillation in an atmosphere of nitrogen. The pyridine comes over at lower temperatures, then, the residue is fractionated and the traction boiling at 95-140" (2 mm.) is collected and designated as the crude portion of Compound Iva. This product is i'ound to contain a small amount of an organic acid, and to remove the latter the product is dissolved in 250 cc. of ether and the ethereal solution shaken vigorously twice with 200 cc. of 5% sodium bicarbonate solution. The ethereal solution is then dried over magnesium sulfate, filtered, the ether removed under reduced pressure and the residue fractionated using a Claisen flask attached to a 30 cm. Vigreux column and the fraction boiling at -103 (1-2 mm.) collected. o 1.5110, dre 0.940. This product fails to give an aldehyde test with iuchsin reagent and absorption spectrum in the ultra-violet region or the spectrum fails to show the presence of an aldehyde group either isolated from or conjugated with the double bonds.

The large range in boiling point (MP-103) in dicates the presence in the product of the cis and trans isomers. The boiling point of the major isomer is about 99 to 103".

PREPARATION or Courotmns V AND Vs, Tnmn STEP, Eousrroxs E'AND EA To about 1 l. of liquid ammonia, in a 3-necked flask equipp d with a Hershberg stirrer and a dropping tunnel, was added 1 g. of hydrated ferric nitrate and l g. oi metallic sodium and the mixture stirred for 1 hour while the temperature was kept at -55 to 'l0. To this mixture was then added a trifle excess over half a mol of metallic sodium and the mixture stirred for half an hour longer. Dry acetylene was then passed through the mixture for several hours or until most of the blue color had assumed a gray-white color. To this mixture was then added, in the course of three hours 46 g. of Compound IV or Compound Iva. in 200 cc. of anhydrous ether taking care that the temperature 01' the mixture never rises above -60 and that the stirring is very rapid. After all of the aldehyde or oxide had been added, the mixture is'ijstirred for 24 hours longer, keeping the temperature between 55 and 'l0. The ammonia is then allowed to evaporate and the brownish residue treated with excess cold aqueous solution of d-tartaric acid and the resulting mixture extracted with ether from which the acetylene carbincl, Compound V or Compound Va, is isolated either by distillation under high vacuum (10- mm.) 01' by preparing its acid phthalate ester in anhydrous pyridine and subsequently saponifying this ester to obtain the pure acetylene carbinol. The phthaiic acid ester had the correct analysis and semi-micro-hydrogenation revealed the presence oi 4 double bonds. The acetylene carbinol also gives a heavy whitish-gray precipitate with ammoniacal alcoholic silver nitrate solution characteristic for acetylenes.

Compounds V and Va have also been prepared. in anhydrous ether solution, by the interaction of Compounds IV and We, with the monogrigl ald of acetylene (HCECmgX), (Equaion PIIIMMTIOI or Comoumis VI, VII MID VII, l ouxrn Sm, Econ-nous H, HA AND I ma IA Five g. of Compound V or Va is dissolved in about 15 g. of anhydrous pyridine and the mixture cooled between and C. To this mix ture is slowly added about 2.2 g. of phosphorus tribromide or a corresponding amount of phosphorus trichlorlde taking care that the temperature does not rise above 0' After half an hour of standing at 0. the mixture is warmed to about 60-70 for minutes, then, without separating Compound VI or We, the mixture is treated with the calculated amount plus 10% excess of 10% alcoholic potash. The mixture is heated on the water bath for half an hour, then poured in four times its volume of water. The aqueous mixture is then extracted several times with ether and the ethereal solution shaken a number of times with a solution of d-tartaric acid to remove the pyridine. Finally, the ether solution is dried over anhydrous magnesium sulfate, filtered, and the ether removed. The residue is nearly pure Compound VII, although for further purification one can distill it under a very high vacuum.

Compound VII may also be prepared by distilling Compound V or Va under reduced pressure (10 -10 mm.) in the presence of small amounts. 1 to 5%, of p-toluene suli'onio acid or naphthalene sulfonic acid (Equation G).

Couromm VIII. Frrrn Srsr,

Eons-non J Five g. of Compound VII in 30 cc. of anhydrous ether is slowhr added to an ethereal solution of the calculated amount or ethyl magnesium bromide and the mixture refluxed in an atmosphere of nitrogen for 5 to 10 hours. To this mixture is then slowly added at 0' with stirring about 2 g. of methyl vinyl ketone which is freshly distilled from small amounts of hydroquinone. The mixture is allowed to stand at room temperature overnight, then poured onto a mixture of ice and ammonium sulfate. Alter the Grignard mixture is completely hydrolyzed, the ethereal layer is separated and dried over anhydrous magnesium sulfate, filtered, and the ether removed under reduced pressure. The residue which is nearly pure Compound VIII may now be used for the next step.

For making Compound VIII from Compound VII via the alkali metal acetylide of Compound VII instead of the Grignard thereof, a. mixture of equal parts of liquid ammonia and anhydrous ethyl ether is prepared and while being maintained at 60' to --'T0 C. small equivalent amounts of Compound VII dissolved in anhydrous ethyl ether and metallic lithium are added whil rapidly stirring. After each addition, the blue color produced is permitted to completely disappear before another addition of Compound VII and lithium is made. After the desired amount of Compound VII and the equivalent amount of lithium have been dissolved, a solution of an equivalent quantity of methyl vinyl ketone in anhydrous ethyl ether is added dropwlse, in the course of an hour, with continued stirring and while maintaining the temperature at 00' to -'l'0' C. The stirring and maintenance of the temperature of 60' to 'l0' C. is then continued for about 10 hours, after which the temperature is allowed to rise and the ammonia to evaporate. The reaction mixture is then neutralized with tartaric acid dissolved in ice cold water and the resulting mixture ex- PRIPAMTIOH 0! tracted several times with ethyl ether. The commagnesium sulfate, then filtered, the ether evaporated under reduced pressure and the residue subjected to a vacuum of from 10- to 10- mm. of mercury to vaporize and remove unreacted Compound VII and methyl vinyl ketone. The residue of this last treatment, on analysis, conforms to the formula of Compound VIII.

Psarmwrrou or Couromm IX, Srxrn S'rsr, EQUATION K der moderately reduced pressure. The residue is nearly pure Compound IX.

The reduction of Compound VIII to Compound IX may also be accomplished under 50-75 atmospheres of hydrogen at not higher than C. and in the presence of an active iron catalyst prepared by leaching the aluminum from an iron-aluminum alloy (Equation K).

Pnsrmarron or Couromm XI, Ssvsm'n Srsr, Eo'osrxous M mp N Although Compound XI may be prepared by the treatment of Compound IX with acetic anhydrlde (Equation L), better yields are obtained by dissolving Compound IX in anhydrous pyridine, cooling to 0', and adding the calculated amount of phosphorus tribromide, Equation M, taking care that the temperature does not rise above 0". The mixture is then warmed to room temperature and kept there for two hours. The mixture is then dissolved in ether and the ethereal solution extracted with a cold 25% solution of acetic acid to remove the pyridine and the phosphorous acid. After the ethereal solution is dried over anhydrous magnesium sulfate, and filtered, the ether is removed under reduced pressure and the residue Compound X, Equation M, is dissolved in glacial acetic acid and treated, in an atmosphere of nitrogen, with freshly fused potassium acetate, Equation N. The mixture is gently heated for about 2 hours to not higher than 100 C., then poured in cold water and extracted with ether. The ethereal solution is separated, dried, and the ether removed. The residue contains considerable amount of Compound XII from which vitamin A can be easily prepared by saponifying it in the usual manner with alcoholic potash (Equation 0). However, Compound XI may be used directly as a vitamin A substitute.

This application is a continuation-in-part of my application Serial No. 353,175, filed August 22. 1940.

I claim:

1. Process for the production of a compound of the formula in which one Y represents H and the other Y represents 0H, which comprises adding methyl vinyl ketone to a solution of a compound of the formula C H: C H 1 in which one Y represents H and the other Y represents OH, the step which comprises introducing into a compound of the formula on CH:

two hydrogen atoms in the presence or a. selective hydrogenation catalyst thereby partially hydrogenating the acetylenic linkage.

3]. As a. new product a. compound of the formu 9.

in which one Y represents H and the other Y represents OH.

4. As a new product a compound of the formula CB: CHI

5. As a. new product a. compound of the formula.

NICHOLAS A. MILAB. 

